The role of p35/CDK5 regulation by miR-15/107 family in Alzheimer’s disease

Alzheimer’s disease (AD) is characterized by the presence of β-amyloid plaques and neurofibrillary tangles of hyperphosphorylated Tau. CDK5 kinase has a key role in abnormal phosphorylation of Tau and β-Amyloid Precursor Protein (APP). CDK5 is activated by p35, encoded by CDK5R1, whose expression can be modulated by miR-103/107, members of the miR-15/107 group, a family of microRNAs involved in AD pathogenesis. In our study, we observed a significant reduction of p35 levels in cells transfected with miR-103/107, -15a and -16 precursors compared to control, while the transfection with antisense LNA molecules for miR-15/107 group leads to increased CDK5R1 transcript and p35 levels, suggesting the action of the whole miR-15/107 family on CDK5R1 expression. We thus hypothesize that reduced levels of miR-15/107 in AD can lead to Tau and APP hyperphosphorylation via upregulation of p35 levels and consequent enhanced CDK5 activity. In order to test this hypothesis, we are studying CDK5R1 and miR-15/107 expression and the CDK5 activity on Tau and APP in frozen brain tissues (hippocampus, temporal cortex and cerebellum) from 12 AD patients and 7 control individuals. In the temporal cortex and hippocampus most miRNAs are downregulated in AD compared to control samples, while in the cerebellum all miRNAs show a similar expression between AD patients and controls, with the exception of miR-107 and miR-15a which are more expressed in AD patients. Interestingly, CDK5R1 mRNA levels are higher in AD hippocampus, but not in temporal cortex and cerebellum tissues, compared to controls. Project supported by FIRB2008 grant (RBFR0895DC_002).